Aging is a major risk factor for metabolic disease and results in a decline in fatty acid oxidation, but the molecular mechanisms for this association are still unclear. The protein Sir2 (Silent Information Regulator) positively regulates aging in model organisms, and its NAD-dependent enzymatic activity connects lifespan with metabolism. Mammals have seven Sir2 homologs (sirtuins;SIRT1-7), which regulate distinct aspects of metabolism. We previously discovered that SIRT4 regulates amino acid metabolism via the inhibition of glutamate dehydrogenase (GDH). Our new results suggest that SIRT4 suppresses fatty acid metabolism, which likely involves several mechanisms, including inhibition of GDH activity in mitochondria, regulation of mitochondrial bioenergetics, and transcriptional repression of genes involved in fatty acid catabolism. We will test this hypothesis through a multi-disciplinary approach, including mouse biology, chemistry and biochemistry. First, using primary hepatocytes from SIRT4 KO mice, we will test the hypothesis that SIRT4 directly suppresses fatty acid oxidation. Then, we will investigate the effect of SIRT4 on mitochondrial energy production from amino acids and fatty acids. Second, we will investigate mechanisms that mediate the regulation of fatty acid oxidation by SIRT4. Third, we will utilize SIRT4 KO mice to test the role of SIRT4 in mammalian lifespan and in the regulation of fatty acid oxidation during aging and metabolic stress. These studies may provide important insights into the molecular regulation of fatty acid oxidation during aging. PUBLIC HEALTH RELEVANCE: The regulation of declining fatty acid oxidation with age remains poorly understood. This proposal investigates the role of SIRT4, as a suppressor of fatty acid oxidation, which may mediate changes in fat metabolism during aging and metabolic dysfunction. These studies have the potential to lead to new treatments of diet and age-associated metabolic syndrome.